Metabolic determinations are an integral part of every drug-discovery and drug-development program. Recent emphasis has been to increase sample throughput while, at the same time, increase information content within assays. To this end, screening for potential drug-drug interactions, overall metabolic stability and metabolite profiles are used early in discovery to select compounds for development. The throttle on the metabolism discovery engine is limited by the time required for data processing and reporting of the information-rich assays used in discovery-stage metabolism studies. In this article I examine how to increase throughput screening in drug discovery using novel liquid chromatography and mass spectrometry as the preferred analytical tool, and potential solutions to maximize output.